6-Bromo-1-hydroxyhexane-1,1-bisphosphonic Acid Monosodium Salt

Abstract

The synthesis of 6-bromo-1-hydroxyhexane-1,1-bisphosphonic acid monosodium salt has been described in detail and characterized by ¹H, ¹³C, ³¹P NMR spectroscopy and high-resolution MS methods. Bisphosphonates are highly important compounds having a lot of medicinal and non-medicinal applications.

1. Introduction

Pyrophosphate which has a P-O-P structure is a natural compound found in mammalian cells [1]. Bisphosphonates (BPs) are synthetic analogs of pyrophosphate with a stable P-C-P backbone. BPs have several medicinal applications such as bone targeting, imaging and diagnostic agents, they also present activity against cancer; however, most known is their use as drugs against osteoporosis [2,3]. BPs have a very high affinity for metal cations, which make them very attractive compounds as ligands for metal organic frameworks (MOFs), water purification and metal concentrating agents [4,5,6]. Different kinds of inorganic–organic hybrid materials have been recently used as platforms for studies investigating the controlled release of BPs [7,8,9].

In the literature there are a few methods for the synthesis of 1-hydroxy-1,1-bisphosphonates; Kieczykowsksi et al. reported a method where carboxylic acid was treated with PCl₃/H₃PO₃ in methanesulfonic acid at 65–70 °C followed by hydrolysis with water [10]. Carboxylic acid chlorides or carboxylic acids activated by catecholborane can also be used as a starting material with tris(trimethylsilyl)phosphite [P(OSiMe₃)₃] at room temperature followed by desilylation with MeOH [11,12]. Maybe the oldest method to synthesize 1-hydroxy-1,1-bisphosphonates concerns preparing tetraesters of BPs followed by acid hydrolysis to obtain the target compounds [13].

2. Results and Discussion

The synthesis method reported by Kieczykowski et al. [10] was first tested to prepare 6-bromo-1-hydroxyhexane-1,1-bisphosphonic acid with no success. Our attempts at isolating target BPs by precipitation were unsuccessful. Because of the quite rough conditions of the synthesis method (PCl₃ in MeSO₃H at 65–70 °C followed by reflux in water -> highly acidic conditions) it was possible, or even likely, that bromine undergoes a substitution reaction (most likely: Br -> OH) and the desired BP becomes impossible to obtain by this method.

6-bromo-1-hydroxyhexane-1,1-bisphosphonic acid mono sodium salt was finally prepared using catecholborane as an activating reagent (see Scheme 1) [11]. 6-bromohexanoic acid was treated with 1 M catecholborane (in THF) followed by the addition of tris(trimethylsilyl) phosphite (2.1 eq), and finally after a bisphosphonation reaction occurred the removal of silyl esters by MeOH. The final compound was precipitated and isolated by the addition of 40% NaOH (1 eq), filtration and re-crystallization from water/EtOH with a 50% yield. A detailed procedure can be found in the Materials and Methods Section.

The target BP was easily characterized by ¹H, ¹³C, ³¹P NMR spectra. In the ¹H NMR spectrum the most characteristic peak was found at 2.01–1.92 ppm (see Supplementary Materials), which is a -CH₂- signal next to a P-C-P carbon. In the ¹³C NMR spectrum the formation of the BP structure was proven by the P-C-P carbon signal at 74.9 ppm, which is in triplet with ¹J_CP = 136.7 Hz, this is a typical coupling constant and field for 1-hydroxy-1,1-bisphoshonates. In the ³¹P NMR spectrum only one peak was observed at 19 ppm which is also typical for 1-hydroxy-1,1-bisphoshonates and proved the high purity of the desired BP (no other phosphorus-containing compounds were among the product, such as H₃PO₄ which can only be observed by ³¹P NMR spectrum).

3. Materials and Methods

3.1. General

All commercial reagents and solvents were used without further purification. ¹H, ³¹P and ¹³C NMR spectra were recorded on a 600 MHz Bruker Avance III HD spectrometer equipped with CryoProbe operating at 600.2, 243.0, and 150.9 MHz, respectively. The solvent residual peak (D₂O) was used as a standard for ¹H measurements, referred to as 4.79 ppm. For the ¹³C NMR measurements CD₃OD was added as a standard, referred to as 49.00 ppm. High-resolution mass spectroscopy (HRMS) was recorded on a q-TOF mass spectrometer (Thermo Scientific, Bremen, Germany) using electrospray ionization (ESI) in the negative mode.

3.2. Synthesis of 6-Bromo-1-hydroxyhexane-1,1-bisphosphonic Acid Monosodium Salt

Synthesis of sodium hydrogen 6-bromo-1-hydroxyhexane-1,1-bisphosphonic acid monosodium salt (1). 1 was synthesized by following a previously reported method with some modifications [11]. 1 M catecholborane solution in THF (10.3 mL, 10.3 mmol) was added to a flask containing 6-bromohexanoic acid (2 g, 10.3 mmol) under a nitrogen atmosphere at room temperature. The mixture was stirred for about 1 h until no more gas evolution was observed. Tris(trimethylsilyl) phosphite (6.5 g, 7.3 mL, 21.8 mmol, 2.1 equiv.) was added and stirring was continued for 20 h. Methanol (55 mL) was added and, after stirring overnight, the solvents were evaporated in vacuo. The residue was dissolved in EtOH (20 mL), cooled in an ice-water bath and 1020 µL (1.0 eq) of 40% NaOH was added with stirring. The rection mixture was placed in the freezer overnight and a formed white precipitate was filtered and re-crystallized from water/EtOH (14 mL/20 mL). 6-bromo-1-hydroxyhexane-1,1-bisphosphonic acid monosodium salt (1.85 g, 50%) was obtained as a white powder. M.p. 248 °C. ¹H NMR (D₂O): δ 3.65 (t, 2H, ³J_HH = 6.8), 2.01–1.92 (m, 2H), 1.93–1.86 (m, 2H), 1.65–1.57 (m, 2H), 1.49–1.42 (m, 2H). ¹³C NMR (D₂O, CD₃OD as ref.) δ 74.9 (t, ¹J_CP = 136.7, P-C-P), 36.1, 34.4, 32.9, 29.1, 23.2 (t, ²J_CP = 6.3). ³¹P NMR (D₂O) δ 19.0. HRMS (ESI-qTOF) m/z: [M − H]⁻ Calcd for C₆H₁₄BrO₇P₂ 338.9398; found: 338.9399.

4. Conclusions

The synthesis and characterization of 6-bromo-1-hydroxyhexane-1,1-bisphosphonic acid monosodium salt has been reported here for the first time. The 6-bromo group gives possibilities for modifications because it is a rather good leaving group. The reported compound may have potential applications in medicinal and non-medicinal fields.